2-Aminomethyleneindanone analgesic agents

ABSTRACT

Novel 2-aminomethyleneindanones having analgesic activity are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 312,693 filedDec. 6, 1972 now U.S. Pat. No. 4,022,836.

BACKGROUND OF THE INVENTION

This invention relates generally to new chemical compounds which areuseful as analgesic agents. More particularly, it is concerned withnovel 2-aminomethyleneindanones which exhibit superior analgesic actionwithout possessing high toxicity.

SUMMARY OF THE INVENTION

The novel compounds of the invention have the formula: ##STR1## and thepharmaceutically-acceptable acid addition salts thereof, wherein R ishydrogen, lower alkyl or phenyl; ##STR2## or -- NH(CH₂)_(n) OR₃, whereinR₃ and R₄ are each hydrogen or lower alkyl, R₅ and R₆ are lower alkyland n is an integer of from 1 to 5; R₁ and R₂ are hydrogen or loweralkyl; R₇ and R₈ are each hydrogen, fluoro or chloro; and R₉ is hydrogenor fluoro. Those compounds wherein Z is ##STR3## particularly2-aminomethylene-1-indanone, are preferred.

A method of alleviating pain utilizing the novel compounds of theinvention is also provided.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention may be prepared by the treatment of a1-indanone with ethyl formate and sodium methoxide in benzene to yieldon acid workup, a 2-hydroxymethylene-1-indanone. The 1-indanone may beappropriately substituted as in formula I wherein R₁ and R₂ are hydrogenor lower alkyl; R₇ and R₈ are each hydrogen, fluoro or chloro; and R₉ ishydrogen or fluoro. The term lower alkyl as used in this specificationis meant to include chains of from 1 to 4 carbon atoms.

The 2-hydroxymethylene-1-indanone is then reacted with the appropriatenitrogen compound e.g. ammonium acetate, dimethyl amine, monomethylamine or aminoethanol, in ethanol or any other suitable solvent to yielda 2-aminomethylene-1-indanone which is then dried and recrystallizedfrom benzene or any other suitable solvent.

Alternatively, the compounds of the invention may be prepared bytreatment of the 1-indanone with the appropriate N,N-dimethyl carboxylicacid amide acetal, RC(OCH₃)₂ NMe₂ or RC(OC₂ H₅)₂ NMe₂, in ethanol or anyother suitable solvent to give the corresponding2-dimethylaminomethylene-1-indanone. This compound is then reacted withthe appropriate nitrogen compound, e.g. ammonium carbonate,monomethylamine or aminoethanol, in ethanol or any other suitablesolvent to yield a 2-aminomethylene-1-indanone.

Acid addition salts may be readily prepared simply by dissolving thefree base in a suitable solvent, e.g. acetone, water, or a loweraliphatic alcohol (ethanol, isopropanol), containing the desired acid,or to which the desired acid is subsequently added. The salts arerecovered by filtration, precipitation with a non-solvent, byevaporation of the solvent or, in the case of aqueous solutions, bylyophilization.

Acids from which pharmaceutically-acceptable addition salts of thecompounds of the invention can be prepared are those which formnon-toxic acid addition salts containing pharmaceutically-acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate orbisulfate, phosphate or acid phosphate, acetate, maleate, fumarate,lactate, citrate, gluconate, saccharate and p-toluene sulfonate salts.

The analgesic activity of these compounds was evaluated by means oftests using thermal nociceptive stimuli, a test using pressurenociceptive stimuli and a test using chemical nociceptive stimuli.

The thermal nociceptive stimuli tests run were the mouse hot plateanalgesic test, modified after Woolfe and MacDonald (J. Pharmacol, Exp.Ther., 80:300-307, 1944) and the mouse tail flick analgesic test,modified after D'Amour and Smith (J. Pharmacol. Exp. Ther., 72:74-79,1941).

The pressure nociceptive stimuli test run was a modification of the tailpinch test as described by Haffner (Deutsch Med. Wschr., 55:731-732,1929).

The chemical nociceptive stimuli test run was the suppression ofirritant-induced writhing, modified after Siegmund et al. (Proc. Soc.Exp. Bio., 95:729, 1957).

The compounds of the invention can be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they may be administeredorally in the form of tablets containing such excipients as starch orlactose, or in capsules either alone or in admixture with excipients orin the form of elixing or suspensions containing flavoring or coloringagents. They may be injected parenterally, for example, intramuscularlyor subcutaneously. For parenteral administration, they are best used inthe form of a sterile aqueous solution which may contain other solutes,for example, enough salts or glucose to make the solution isotonic.

With respect to dosage levels, a broad dosage range of 25 to 500 mg. foradults is appropriate, a particularly preferred range being from 50 to150 mg., such dosage being administrable up to four times a day. Thephysician in any event will determine the actual dosage which will bemost suitable for an individual patient and it will vary with age, theweight and response of the particular patient. The above dosages areexemplary of the average host. There can, of course, be individual caseswhere higher or lower dosage ranges are merited, and such are within thescope of this invention.

The invention is illustrated by the following Examples.

EXAMPLE I Preparation of 2-Hydroxymethylene-1-Indanone

To a mechanically stirred suspension of ethyl formate (600 ml.) andsodium methoxide (430.0 gm., 7.95 mole) in 3.7 liters of dry benzene, ina nitrogen charged 22 liter round bottom flask, cooled with an ice/H₂ Obath to 5° C, was added 1-indanone (500 gm., 3,785 mole) dissolved in3.5 liter of benzene. The 1-indanone was added dropwise over a period of1.5 hrs., maintaining the reaction temperature below 8° C. The color ofthe reaction mixture gradually changed from tan to a dark, purple-blackover the course of the addition with the formation of a precipitate.Upon completion of the addition the ice-bath was removed and thereaction mixture was allowed to warm to approximately 15° C over 4.5hours. The viscous, purple-black reaction mixture was hydrolyzed by theaddition of ice/water, diluted with an equal volume of water and heatedin a steam bath to 50° C giving a black solution. The benzene layer wasseparated and washed with 1 liter of 5% sodium hydroxide. The wash wasadded to the aqueous layer and back extracted with two 2 liter portionsof ether.

The above reaction procedure was repeated two more times.

The combined aqueous layers from the three reactions were poured onto anice/HCl mixture (10.7 liters 12NHCl) giving an off white precipitatewhich in filtration and air drying (15-20 min.) gave a water wet cake(3.7 kg.) of 2-hydroxymethylene-1-indanone, m.p. 115°-116° C (Lit m.p.112°-113° C, J. Amer. Chem. Soc., 66:218, 1944). This product wassufficiently pure for the subsequent reaction. Preparation of2-Aminomethylene-1-Indanone

To a stirred solution of 2-hydroxy-methylene-1-indanone (1.6 kg. as a3.7 kg. wet cake) dissolved in ethanol (30 liters), and under a nitrogenatmosphere was added ammonium acetate (1.92 kg. 24.8 mole). After eighthours the reaction was complete and the ethanol was removed by vacuumdistillation. The reaction mixture was cooled to room temperature andafter filtration and air drying (1 hr.) yielded crude2-aminomethylene-1-indanone (I) as orange crystals. The crystals werethen dissolved in a minimum amount of hot ethanol and the solution wasdecolorized with activated charcoal. Crystals appeared in the filtrateand after cooling overnight at 5° C, the reaction mixture was filteredyielding 960 gm. of compound (I) as light orange crystals. The filtratewas again treated with activated charcoal and recrystallized providingan additional 200 gm. of compound (I). The combined sample (1160 gm.)was milled giving a fine yellowish powder which was dried at 50° C/25mm/Hg for 48 hours. A sample (50 gm.) of this material wasrecrystallized three times from ethanol to give2-aminomethylene-1-indanone (15 gm.), m.p. 166°-168° C.

Anal. Calc'd. for C₁₀ H₉ ON: C,75.45; H,5.70; N,8.80; Found: C,75.13;H,5.70; N,8.77.

EXAMPLES II TO XII

The following compounds were made by the procedure described in ExampleI, but with the use of the appropriately substituted starting materials:

    __________________________________________________________________________     ##STR4##                                                                                        Analysis (Calculated in Brackets)                          Example                                                                              Formula     % C    % H  % N                                            __________________________________________________________________________    II     C.sub.11 H.sub.11 ON                                                                      76.63  6.41 8.10                                                              (76.37 6.46 8.04)                                          III    C.sub.16 H.sub.13 ON                                                                      81.32  5.41 5.69                                                              (81.68 5.57 5.95)                                          IV     C.sub.12 H.sub.13 ON                                                                      76.96  7.05 7.54                                                              (76.97 7.00 7.48)                                          V      C.sub.10 H.sub.8 ONCl                                                                     62.0   4.33 7.40                                                              (62.23 4.18 7.26)                                          VI     C.sub.10 H.sub.8 ONCl . H.sub.2 O                                                         56.81  4.79 6.52                                                              (56.92 4.78 6.64)                                          VII    C.sub.10 H.sub.7 ONF                                                                      68.47  3.99 8.04                                                              (68.64 4.01 7.96)                                          VIII   C.sub.11 H.sub.11 ON                                                                      76.29  6.57 8.17                                                              (76.27 6.40 8.09)                                          IX     C.sub.12 H.sub.13 ON                                                                      77.03  6.82 7.43                                                              (76.98 7.00 7.48)                                          X      C.sub.12 H.sub.12 ONCl                                                                    (64.59 5.39 6.48                                                              (65.22 5.47 6.34)                                          XI     C.sub.12 H.sub.12 ONCl                                                                    65.38  5.58 5.99                                                              (65.02 5.46 6.32)                                          XII    C.sub.12 H.sub.12 ONCl                                                                    60.83  5.17 5.90                                                              (60.82 5.10 5.90)                                          __________________________________________________________________________                          Crystallization                                         Example                                                                            Substituents     Solvent   m.p. ° C                               __________________________________________________________________________    II   Z = NH.sub.2 ; R = CH.sub.3 ; R.sub.1,R.sub.2,                                                 Ethyl Acetate                                                                           172-4                                              R.sub.7,R.sub.8,R.sub.9 = H                                              III  Z = NH.sub.2 ; R = C.sub.6 H.sub.5 ; R.sub.1,R.sub.2,                                          CH.sub.3 CN/H.sub.2 O                                                                    69-71                                             R.sub.7,R.sub.8,R.sub.9 = H                                              IV   Z = NH.sub.2 ; R.sub.1,R.sub.2 = CH.sub.3 ; R,                                                 Benzene   143-5                                              R.sub.7,R.sub.8,R.sub.9 = H                                              V    Z = NH.sub.2 ; R,R.sub.1,R.sub.2,R.sub.7,                                                      Ethyl Acetate/                                                                          115-9                                              R.sub.9 = H; R.sub.8 = Cl                                                                      Hexane                                                  VI   Z = NH.sub.2 ; R.sub.7 = Cl; R,R.sub.1,                                                        Ethyl Acetate/                                                                          117-20                                             R.sub.2,R.sub.8,R.sub.9 = H                                                                    Hexane                                                  VII  Z = NH.sub.2 ; R.sub.9 = F; R,R.sub.1,                                                         Benzene   179-82                                             R.sub. 2,R.sub.7,R.sub.8 = H                                             VIII Z = NHCH.sub.3 ; R,R.sub.1,R.sub.2,R.sub.7,                                                    None      194-6                                              R.sub.8,R.sub.9 = H                                                      IX   Z = N(CH.sub.3).sub.2 ; R,R.sub.1,R.sub.2,                                                     Benzene/Hexane                                                                          157-9                                              R.sub.7,R.sub.8,R.sub.9 = H                                              X    Z = N(CH.sub.3).sub.2 ; R.sub.8 = Cl; R,                                                       Benzene/Hexane                                                                          149-50                                             R.sub.1,R.sub.2,R.sub.7,R.sub.8 = H                                      XI   Z = N(CH.sub.3).sub.2 ;R,R.sub.1,R.sub.2,                                                      Benzene/Hexane                                                                          183-5                                              R.sub.8,R.sub.9 = H; R.sub.7 = Cl                                        XII  Z = NHCH.sub.2 CH.sub.2 OH; R.sub.8 = Cl;                                                      Isopropyl Alcohol                                                                       164-6                                              R,R.sub.1,R.sub.2,R.sub.7,R.sub.9 = H                                    __________________________________________________________________________

EXAMPLE XIII Preparation of 2-Dimethylaminomethylene-1-indanone

To a 2 liter 3-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer were added 50.0 gm. (0.38 mole) of1-indanone, 750 ml. of ethanol and 67.8 gm. (0.57 mole) ofN,N-dimethylformamide dimethylacetal under a nitrogen atmosphere. Theresulting solution was boiled under reflux for 5 hrs. and stirredovernight at room temperature. The reaction mixture was then taken up in1 l. of hot benzene, treated with activated charcoal, filtered, andallowed to crystallize. A second recrystallization from benzene yielded45.7 gm. of 2-dimethylaminomethylene-1-indanone, m.p./159°-161° C. Anadditional 18.3 gm., m.p. 157°-60° C, was recovered from the motherliquors of the first crystallization.

A sample of 2-dimethylaminomethylene-1-indanone, m.p. 157°-59° C frombenzene/hexane, which was prepared in a similar manner was analyzed.

Anal. Calc'd. for C₁₂ H₁₃ ON: C, 76.98; H, 7.00; N, 7.48; Found: C,77.03; H, 6.82; N, 7.43.

Preparation of 2-Aminomethylene-1-indanone

A mixture of 54.0 gm. (0.29 mole) of2-dimethylaminomethylene-1-indanone, 255 gm. of ammonium carbonate, 900ml. of ammonium hydroxide, and 450 ml. of ethanol was stirred at roomtemperature for 6 days, then concentrated to about 700 ml. and pouredonto 1500 ml. of cold water. The resulting solid was filtered and driedat 50° C (25 mm.) to give 45.4 gm. of impure2-aminomethylene-1-indanone, m.p. 159°-60° C, which was partitionedbetween 2 liters of ethyl acetate and 1 liter of water to remove anyremaining inorganic salts. The ethyl acetate layer was dried overmagnesium sulfate, filtered and concentrated under reduced pressure togive a solid which was recrystallized from ethyl acetate/acetone toyield 28.1 gm. of yellow crystals of 2-aminomethylene-1-indanone, m.p.163°-65° C.

Anal. Calc'd. for C₁₀ H₉ ON: C, 75.45; H, 5.70; N, 8.80; Found: C,75.31; H, 5.77; N, 8.83.

EXAMPLE XIV Preparation of 5-chloro-2-dimethylaminomethylene-1-indanone

A solution of 10.0 gm. (0.06 mole) of 4-chloro-1-indanone and 10.7 gm.(0.09 mole) of N,N-dimethylformamide dimethylacetal in 250 ml. ofabsolute alcohol was boiled under reflux for 20 hrs., then an additional5.35 gm. (0.045 mole) of N,N-dimethylformamide dimethylacetal was added.The reaction mixture was refluxed for an additional 5 hrs., cooled, andconcentrated under reduced pressure to give a red solid which was takenup in benzene, treated with activated charcoal, filtered, and evaporatedunder reduced pressure to give a light red solid. Two morerecrystallizations from benzene/hexane gave 8.3 gm. of5-chloro-2-dimethylaminomethylene-1-indanone, m.p. 148°-149.5° C.

One additional recrystallization from benzene gave an analytical sample,m.p. 149°-50° C.

Anal. Calc'd. for C₁₂ H₁₂ ONCl; C, 65.22; H, 5.47; N, 6.34; Found: C,64.59; H, 5.39; N, 6.48.

Preparation of 5-chloro-2-(2-hydroxyethyl)aminomethylene-1-indanone

A solution of 1.5 gm. (0.007 mole) of5-chloro-2-dimethylaminomethylene-1-indanone, 1.3 gm. (0.021 mole) of2-aminoethanol, 5 drops of acetic acid, and 20 ml. of ethanol wasstirred overnight at room temperature under a nitrogen atmosphere. Thepink precipitate was filtered, washed with a small amount of ethanol,and recrystallized from isopropyl alcohol to give 0.80 gm. of whitecrystals of 5-chloro-2-(2-hydroxyethyl)aminomethylene-1-indanone, m.p.164°-166° C.

Anal. Calc'd for C₁₂ H₁₂ NCl: C, 60.82; H, 5.10; N, 5.91; Found: C,60.83; H, 5.17; N, 5.90.

EXAMPLE XV Following the procedure described in Example I, but using theappropriately substituted starting materials the following compounds maybe made. ##STR5## Z = NH₂ ; R, R₁, R₂, R₈, R₉ = H; R₇ = F Z = N(CH₃)₂ ;R, R₁, R₂, R₇, R₉ = H; R₈ = F

Z = n(n-C₄ H₉)₂ ; R, R₁, R₂, R₇, R₈, R₉ = H

Z = n(c₂ h₅)₂ ; r, r₁, r₂, r₇, r₈, r₉ = h

z = nh₂ ; r, r₇, r₈, r₉ = h; r₁, r₂, = n-C₄ H₉

Z = nh(ch₂)₅ nh₂ ; r, r₁, r₂, r₇, r₈, r₉ = h

z = nh(ch₂)₂ nhch₃ ; r, r₁, r₂, r₈, r₉ = h; r₇ = cl

Z = nhch₂ nh₂ ; r, r₁, r₂, r₇, r₈, r₉ = h

z = nhch₂ oh; r, r₁, r₂, r₇, r₈, r₉ = h

z = nh(ch₂)₅ oh: r, r₁, r₂, r₇, r₈, r₉ = h

z = nhch₂ och₃ ; r, r₁, r₂, r₇, r₉ = h; r₈ = cl

The above compounds may also be prepared by the procedure described inExample XIII but using the appropriately substituted starting materials.

EXAMPLE XVI

The following tests were run in order to indicate the analgesicproperties of the compounds of the invention

Mouse hot plate analgesic test (HP)

The method used was modified after Woolfe and MacDonald (1944). Acontrolled heat stimulus was applied to the feet of mice on a one-eighthinch thick aluminum plate. A 250 w reflector infrared heat lamp wasplaced under the bottom of the aluminum plate; a thermal regulator,connected to thermistors on the plate surface, programmed the heat lampto maintain a constant temperature of 57° C. Each mouse was dropped intoa 61/2 D. glass cylinder resting on the hot plate, and timing began whenthe animal's feet touched the plate. The mouse was observed at 0.5 and 2hr. after treatment with test compound, for the first "flicking"movements of one or both hind feet, or until 10 sec. elapsed withoutsuch movements.

Mouse tail flick analgesic test (TF)

The tail flick test in mice was modified after D'Amour and Smith (1941),using controlled high intensity heat applied to the tail.

Each mouse was placed in a snug-fitting metal cylinder, with the tailprotruding through one end. This cylinder was arranged so that the taillay flat over a concealed heat lamp. At the onset of testing, analuminum flag over the lamp was drawn back, allowing the light beam topass through the slit and focus onto the end of the tail. A timer wassimultaneously activated. The latency of a sudden flick of the tail wasascertained. Untreated mice usually reacted from 3-5 sec. after exposureto the lamp. The end point was 10 sec. Each mouse was tested at 0.5 and2 hr. after drug treatment.

Effect on the Haffner tail pinch procedure (RTC) A modification of theprocedure of Haffner (1929) was used to ascertain the effects of testcompounds on aggressive attacking responses elicited by a stimuluspinching the tail. A Johns Hopkins 21/2 inches "bulldog" clamp wasclamped onto the root of the rat's tail prior to drug treatment, andagain at 0.5, 1 and 2 hr. after drug treatment. The endpoint at eachtrial was clear attacking and biting behavior directed towards theoffending stimulus; the clamp was removed to 30 sec. if attacking hadnot occurred by then, and the latency of response was recorded as 30sec.

Suppression of irritant-induced writhing (PBQ)

A group of 10 to 20 mice were pretreated subcutaneously with saline orwith test compounds. One hour later each group was treated withphenylbenzoquinone (2 mg/kg; 5% in ethanol), an intraperitoneal irritantknown to produce writhing (repetitive abdominal contractions). At 10minutes after phenylbenzoquinone administration, known to correspond topeak writhing time, the mice were observed for 2 min. for the presenceor absence of writhing.

The results obtained are as follows:

    __________________________________________________________________________         HP Test   TF Test   RTC Test       PBQ - %                                    % Protected                                                                             % Protected                                                                             % Protected    Protected                             Compound                                                                           0.5 hr                                                                             2 hr 0.5 hr                                                                             2 hr 0.5 hr                                                                             1 hr                                                                              2 hr  at 100 mg/kg                          __________________________________________________________________________    I    40   80   10   60   >30  >30 >30   40                                    II   20   20   10   0    >30  >30 >30   --                                    III  40   40   10   0    4    4   6     --                                    IV   30   0    50   0         --         0                                    V    40   0    80   15   13   3   3      0*                                   VI   100  60   80   0    >30  >30 >30   60                                    VII  80   20   40   0    >30  10  11    20                                    VIII 40   40   20   20        --        40                                    IX   40   20   20   0    >30  >30 >30   40                                    X    40   0    80   10   >30  >30 >30   20                                    XI   60   40   50   0    >30  >25 >30   100                                   XII  20   40   70   10   15   13  11    100*                                  __________________________________________________________________________     *at 320 mg./kg.                                                          

What is claimed is:
 1. A method of alleviating pain comprising theadministration to a pain afflicted host of a pain alleviating effectiveamount of a compound of the formula: ##STR6## or apharmaceutically-acceptable acid addition salt thereof, wherein R ishydrogen, lower alkyl or phenyl; ##STR7## wherein R₃ and R₄ are eachhydrogen or lower alkyl, R₅ and R₆ are lower alkyl and n is integer offrom 1 to 5; R₁ and R₂ are hydrogen lower alkyl; R₇ and R₈ are eachhydrogen, fluoro or chloro; and R₉ is hydrogen or fluoro.
 2. The methodof claim 1 wherein said compound is 2-aminomethylene-1-indanone.